TRIAZOLE COMPOUNDS THAT MODULATE HSP90 ACTIVITY

摘要

The present invention relates to substituted triazole compounds and compositions comprising substituted triazole compounds. The invention further relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for preventing or treating hyperproliferative disorders, such as cancer, in a subject in need thereof comprising administering to the subject a substituted triazole compound of the invention, or a composition comprising such a compound.

主权项

1. A compound represented by the following structural formula: or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein:
X42 is CR44 or N;R41 is —H, —OH, —SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, —NR10R11, —OR7, —C(O)R7, —C(O)OR7, —C(S)R7, —C(O)SR7, —C(S)SR7, —C(S)OR7, —C(S)NR10R11, —C(NR8)OR7, —C(NR8)R7, —C(NR8)NR10R11, —C(NR8)SR7, —OC(O)R7, —OC(O)OR7, —OC(S)OR7, —OC(NR8)OR7, —SC(O)R7, —SC(O)OR7, —SC(NR8)OR7, —OC(S)R7, —SC(S)R7, —SC(S)OR7, —OC(O)NR10R11, —OC(S)NR10R11, —OC(NR8)NR10R11, —SC(O)NR10R11, —SC(NR8)NR10R11, —SC(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —C(O)NR10R11, —NR8C(O)R7, —NR7C(S)R7, —NR7C(S)OR7, —NR7C(NR8)R7, —NR7C(O)OR7, —NR7C(NR8)OR7, —NR7C(O)NR10R11, —NR7C(S)NR10R11, —NR7C(NR8)NR10R11, —SR7, —S(O)pR7, —OS(O)pR7, —OS(O)pOR7, —OS(O)pNR10R11, —S(O)pOR7, —NR8S(O)pR7, —NR7S(O)pNR10R11, —NR7S(O)pOR7, —S(O)pNR10R11, —SS(O)pR7, —SS(O)pOR7, —SS(O)pNR10R11, —OP(O)(OR7)2, or —SP(O)(OR7)2;R42 is —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, —C(O)R7, —(CH2)mC(O)OR7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —S(O)pR7, —S(O)pOR7, or —S(O)pNR10R11;R43 and R44 are, independently, —H, —OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —C(O)R7, —C(O)OR7, —OC(O)R7, —C(O)NR10R11, —NR8C(O)R7, —SR7, —S(O)pR7, —OS(O)pR7, —S(O)pOR7, —NR8S(O)pR7, —S(O)pNR10R11, or R43 and R44 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl;R45 is —H, —OH, —SH, —NR7H, —OR26, —SR26, —NHR26, —O(CH2)mOH, —O(CH2)mSH, —O(CH2)mNR7H, —S(CH2)mOH, —S(CH2)mSH, —S(CH2)mNR7H, —OC(O)NR10R11, —SC(O)NR10R11, —NR7C(O)NR10R11, —OC(O)R7, —SC(O)R7, —NR7C(O)R7, —OC(O)OR7, —SC(O)OR7, —NR7C(O)OR7, —OCH2C(O)R7, —SCH2C(O)R7, —NR7CH2C(O)R7, —OCH2C(O)OR7, —SCH2C(O)OR7, —NR7CH2C(O)OR7, —OCH2C(O)NR10R11, —SCH2C(O)NR10R11, —NR7CH2C(O)NR10R11, —OS(O)pR7, —SS(O)pR7, —NR7S(O)pR7, —OS(O)pNR10R11; —SS(O)pNR10R11, —NR7S(O)pNR10R11, —OS(O)pOR7, —SS(O)pOR7, —NR7S(O)pOR7, —OC(S)R7, —SC(S)R7, —NR7C(S)R7, —OC(S)OR7, —SC(S)OR7, —NR7C(S)OR7, —OC(S)NR10R11, —SC(S)NR10R11, —NR7C(S)NR10R11, —OC(NR8)R7, —SC(NR8)R7, —NR7C(NR8)R7, —OC(NR8)OR7, —SC(NR8)OR7, —NR7C(NR8)OR7, —OC(NR8)NR10R11, —SC(NR8)NR10R11, or —NR7C(NR8)NR10R11; andR7 and R8, for each occurrence, is independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;R10 and R11, for each occurrence, is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;R26 is a lower alkyl;R35 and R36, for each occurrence, is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, or R35 and R36, together with N to which they are attached form a 5 to 7 membered heterocyclic ring;m, for each occurrence, is independently, 1, 2, 3, or 4;p, for each occurrence, is independently, 1 or 2.